For living tissue regeneration, various methods including the administration of pharmaceuticals and surgical operations have heretofore been attempted but no agents or therapeutic methods have proved fully effective in regeneration of injured or defective tissue. In recent years, a large number of reports have been published on the migration and accumulation of stem cells to the injured sites of tissue. It has been reported that when mesenchymal stem cells (hereinafter sometimes abbreviated to MSCs) or cells in umbilical cord blood are injected to traumatic brain injury intravenously or MSCs are injected by intraarterial route, the injected cells accumulate in the injured brain (Mahmood A et al., Neurosurgery 2001;49:1196-203; discussion 203-4; Lu D et al., Cell Transplantation 2002;11:275-81; Lu D et al., J Neurotrauma 2001;18:813-9). It has also been reported that intrastriatal transplantation of bone marrow nonhematopoietic cells improves functional recovery in mice with brain injury (Li Y et al., J Cereb Blood Flow Metab 2000;20:1311-9). In addition, it was found that intravenous infusion of MSCs in model rats with middle cerebral artery occlusion enabled them to recover their neurological severity scores compared with untreated groups, with some rats being recognized to show differentiation of the transplanted MSCs into neurons (Chen J et al., Stroke 2001;32:1005-11).
It has also been reported that when bone marrow cells are injected intravenously into an experimentally induced fractures, the injected bone marrow cells “home” to the bone marrow and localize to fracture callus in a mouse (Devine M J et al., J Orthop Res 2002;20:1232-9). However, it has not yet become clear how the cells recognize an injured site in the process of their migration and accumulation.
Extensive in vitro reviews have been made to date about individual migration and accumulation factors for various cells. PDGF (platelet-derived growth factor) BB is known as a paracrine-like migration and accumulation factor for various kinds of adhesive cells (Yu J et al., Biochem Biophys Res Commun 2001;282:697-700). PDGF-BB is an especially potent migration and accumulation factor for endothelial cells or mesangial cells (Hirschi K K et al., Circ Res 1999;84:298-305; Kohno M et al., J Am Soc Nephrol 1999;10:2495-502). FGF2 (fibroblast growth factor-2) is known as an autocrine-like migration and accumulation factor (Kondo H et al., Biochem Biophys Res Commun 2000;272:648-52) and its migration and accumulation ability and mechanism in endothelial cells, osteoblasts, fetal fibroblasts, etc. are being reviewed (Shono T et al., Exp Cell Res 2001;264:275-83; Mayr-Wohlfart U et al., Bone 2002;30:472-7; Liu J et al., Oncogene 1999;18:6700-6). EGF (epidermal growth factor) is also reported as a migration and accumulation factor for several cells (Chen P et al., J Cell Biol 1994;124:547-55). Recently, the EGF's action mechanism in the migration and accumulation of cancer cells is also being reviewed (Kawahara E et al., Exp Cell Res 2002;272:84-91). HB-EGF (heparin-binding epidermal growth factor) which is a member of EGF family has been reported to enhance the survival, proliferation, as well as migration and accumulation of epidermal cells (Takemura T et al., J Biol Chem 1997;272:31036-42; Barnard J A et al., J Biol Chem 1994;269:22817-22; Wilson SE et al., Exp Eye Res 1996;62:325-7) but no review has been made except for the epidermal cells. TGF-α has been reported to have approximately 30-40% homology with EGF and as taking part in tissue repair via the EGF receptor (Schultz G et al., J Cell Biochem 1991;45:346-52). TGF-α has been reported to be mainly responsible for the proliferation as well as migration and accumulation of keratinocytes (Cha D et al., J Invest Dermatol 1996;106:590-7) but no reports have been made concerning other cells.
Thrombin is known as an enzyme that coagulates blood by converting fibrinogen to fibrin, and it has recently been reported as enhancing the proliferation as well as migration and accumulation of Swiss 3T3 cells by inducing the clustering of their EGF receptors (Crouch M F et al., J Cell Biol 2001;152:263-73). It has also been reported as enhancing the migration and accumulation of human renal cancer cells (Kaufmann R et al., Cancer Lett 2002;180:183-90). Atrial natriuretic peptide (ANP) is a peptide composed of 28 amino acids that are synthesized in the heart and occurs in circulating blood. ANP has a potent diuresis and vasodilation effect, vascular smooth muscle relaxation effect, a rennin-angiotensin system suppressing effect, a sympathetic nerve suppressing effect, and the like, and it has been reported that ANP suppresses the migration and accumulation of endothelial cells, as exemplified by suppression of the PDGF mediated migration and accumulation of vascular smooth muscle cells (Ikeda M et al., Arterioscler Thromb Vasc Biol 1997;17:731-6) and in the case of suppressing the VEGF's mediated migration and accumulation of endovascular cells (Pedram A et al., Endocrinology 2001;142:1578-86). Leptin, a 16-kD circulating protein secreted mainly by adipose tissue, is a product of the obese gene. Leptin has been reported to enhance the proliferation, migration and accumulation, tube formation, etc. of human endothelial cells in vitro and it has been reported that leptin probably induces endochondral ossification by inducing angiogenesis (Kume K et al., J Histochem Cytochem 2002;50:159 69). It has also been reported that leptin enhances collagen synthesis and mineralization of iliac osteoblasts (Gordeladze J O et al., J Cell Biochem 2002;85:825-36). However, nothing is known about the migration ability of those factors with respect to MSCs.